Before entering the video games industry, Druckmann majored in criminology. While attempting a course in programming, he realised "people make games", inspiring him to find a job based in game design. Deciding to switch majors, he enrolled for the Entertainment Technology masters in Carnegie Mellon University and sought an internship at video game development studio Naughty Dog by "harassing" co-president Jason Rubin, who "made the mistake" of giving him his number. He eventually succeeded and was brought on as a stint programmer on Jak 3 in early 2004, one year into his Carnegie Mellon's masters program.[6][7] He reported;y learned English, finding the words in a dictionary, because he was interested in video games.[8]

Afterwards, Druckmann went on to continue programming work on Jak X: Combat Racing before eventually landing a position in design for Uncharted: Drake's Fortune. This was Druckmann's initial aim, but studio veteran Evan Wells (now co-president of the studio) restrained from placing him in design originally because he was "hired to do programming" so had to do programming work as a part of his job capacity; after intermittently working after-hours over the course of the next year on design projects (once completed with his programming duties) and frequenting them to Wells for review, however, Wells finally concluded that he was "an excellent designer as well" and brought him on to the design team for Uncharted for the first time,[9] for which he also did additional writing.[3]

Following the success of Drake's Fortune in 2007, Druckmann was cast as co-lead game designer of Uncharted 2: Among Thieves alongside Richard Lemarchand, in addition to serving as co-writer alongside co-workers Josh Scherr and creative director Amy Hennig.[3] He was also one of three designers (the others being Amy Hennig and Bruce Straley) who conjured the idea of the now heralded[10][11]Where Am I? chapter, which featured main protagonist Nathan Drake exploring a peaceful Tibetan village after losing consciousness due to exsanguination in a snowstorm days before.[12] Months later, in October of 2009, Among Thieves was released to critical acclaim.

By 2011, having decided against rebooting the Jak and Daxter series, Druckmann successfully pitched the initial ideas for The Last of Us alongside Bruce Straley, and began work as creative director over the story. While making the game, he worked closely with Troy Baker and Ashley Johnson to bring the characters to life, taking the flexible stance of trying several ideas the pair and others suggested to "see what happens", regardless of the results believing that "out of all that, we [got] these little, magical moments that bring the game together". He created the story by starting in the middle before taking a chronological approach from start to finish once the plot had been secured.[13]. Baker, after working on the game, openly stated Druckmann was the best director he ever worked with.[14]

Druckmann also wrote the script for the DLC of the game, Left Behind, provided in-game commentary with Baker and Johnson for the cutscenes in the Remastered edition of the game and was present at The Last of Us: One Night Live. There, he unveiled a special ending for the audience members, depicting a snippet of Joel and Ellie's life after the game.[15] He received praise for the characters he had conceived, particularly in regards to the advancement of LGBTQ characters in video games through the characters of Bill, Riley and Ellie and the craft of strong, non-sexualised, female characters, something he felt passionate about as he desired to provide role models for women as well as men.

Druckmann was even asked to do a talk regarding the game at 2013 IGDA in Toronto. While there, he recommended books he felt every writer should read if they were going into the industry as well as disclosing concept art for the proposed Jak and Dakter reboot. He talked about how the story of The Last of Us evolved, ranging from the character Tess initially being the antagonist to Marlene being a doctor but admitted it was always going to be about Joel and Ellie as, in Druckmann's words, "it was vital we [the staff] finished their story arc...you have to be honest and true to the story you want to tell which was, at its core, about the bond between parent and child". [16]

After The Last of Us, Druckmann and his partner Straley returned to the Uncharted series (having not worked on Uncharted 3: Drakes Deception) to co-direct Uncharted 4: A Thief's End, replacing the previous writers. Having proved story orientated games could be successful with their previous title, they expanded on what they did in Uncharted 2: Among Thieves, making the fourth game more realistic and character focused, namely through the introduction of Nathan Drake's brother, Sam Drake, making him an ally rather than a surprise villain, and included several segments of the story to portray a "normal life", moving away from the completely adventurous world of previous Uncharted games. To further their aims of creating realism, they designed the main character, Nathan Drake, to appear to barely make the leaps he makes towards walls and had him grunt and comment on the difficulty of such.[17] They also tried to make the climbing sequences long and engaging through adding a stamina meter for Nathan as he's climbing to add tension. However, Druckmann revealed they realised the climbing soon overshadowed the shooting mechanics, so they cut it out but lacked the time to shorten the length of the climbing sequences, leading to segments in the game that the team desired to remove, but could not.[18]

As Straley will not return to assist with directing the sequel to The Last of Us, "taking a year out" after the pair finished working on the DLC for Uncharted: A Thief's End,[19] and subsequently left Naughty Dog[20], Druckmann announced on Twitter (December 3, 2016) that he will be co-writing the script with Westworld writer Halley Gross.[21] He unveiled it further at PSX 2016 in December, showcasing a trailer he had shot with Baker and Johnson very early in the game's development along with some initial concept art and a snapshot of the new engine Naughty Dog were using to create the characters.